WO2011008663A1 - Gpr119 agonists - Google Patents

Gpr119 agonists Download PDF

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Publication number
WO2011008663A1
WO2011008663A1 PCT/US2010/041645 US2010041645W WO2011008663A1 WO 2011008663 A1 WO2011008663 A1 WO 2011008663A1 US 2010041645 W US2010041645 W US 2010041645W WO 2011008663 A1 WO2011008663 A1 WO 2011008663A1
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WIPO (PCT)
Prior art keywords
mmol
methanesulfonyl
mixture
tetrahydro
compound
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PCT/US2010/041645
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English (en)
French (fr)
Inventor
David Gene Barrett
Ana Belen Bueno Melendo
Jeffry Bernard Franciskovich
Bin Liu
Kumiko Takeuchi
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Eli Lilly And Company
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Priority to CA2764906A priority Critical patent/CA2764906C/en
Priority to KR1020127000996A priority patent/KR101365854B1/ko
Priority to SG2012002523A priority patent/SG177646A1/en
Priority to CN201080031375.4A priority patent/CN102471313B/zh
Priority to EA201270169A priority patent/EA020540B1/ru
Priority to MA34531A priority patent/MA33428B1/fr
Priority to MX2012000704A priority patent/MX2012000704A/es
Priority to EP10734412A priority patent/EP2454251A1/en
Priority to JP2012520691A priority patent/JP5715127B2/ja
Priority to BRPI1015921A priority patent/BRPI1015921A2/pt
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU2010273642A priority patent/AU2010273642B2/en
Priority to NZ597125A priority patent/NZ597125A/xx
Publication of WO2011008663A1 publication Critical patent/WO2011008663A1/en
Priority to IL216776A priority patent/IL216776A0/en
Priority to TNP2012000002A priority patent/TN2012000002A1/en
Priority to ZA2012/00227A priority patent/ZA201200227B/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • GPRl 19 is a G-protein-coupled receptor largely confined in humans to pancreatic ( ⁇ -cells) and intestinal tissues (enteroendocrine cells) and has been studied and described using various synonyms including SNORF25, RUP3, GPCR2, 19AJ, OSGPRl 16 and glucose-dependent insulinotropic receptor.
  • GPRl 19 The pharmacology and therapeutic potential for GPRl 19 has been reviewed recently (Br. J. Pharmacol. 2008, 153, S76-S81), disclosing GPRl 19 as an interesting target for the treatment of diabetes and obesity.
  • GPRl 19 A number of synthetic agonists of GPRl 19 have been disclosed for the treatment of diabetes and obesity, for example those disclosed in WO 09/038974. There remains a need for alternative GPRl 19 agonists as antidiabetic and antiobesity therapies.
  • Oral administration is typically the preferred route of administration for antidiabetic and antiobesity therapies.
  • compounds to display good oral bioavailability they typically must have sufficient aqueous solubility to allow absorption, and sufficient metabolic stability to minimize first pass degradation in the liver.
  • the compounds of Formula I have been found to be agonists of GPRl 19 in vitro. Certain compounds of the present invention have been shown to stimulate GIP secretion in vivo. Certain compounds of the present invention exhibit greater potency than existing agonists. Certain compounds of the present invention have good oral bioavailability.
  • the present invention is directed to compounds of Formula I which are agonists of the G-protein-coupled receptor GPRl 19, pharmaceutical compositions containing them as active ingredient, and to their use in the treatment or prevention of diabetes or obesity, in particular Type II diabetes.
  • the present invention provides a compound of the formula: X18674
  • X is selected from N and CH;
  • R a is selected from F and CF3;
  • R and R° are independently selected from F and methyl or combine to form a C3-5 cycloalkyl ring;
  • R 1 is selected from H and methyl
  • R 2 is selected from H and F
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes and obesity.
  • the present invention further provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes or obesity.
  • the present invention further provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diabetes or obesity
  • the present invention also provides a method for the treatment of diabetes and obesity, which comprises administering an effective amount of a compound of Formula I, X18674
  • the present invention further provides a method for the treatment of diabetes or obesity, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof. It is preferred that the compounds of the present invention be used in the treatment of diabetes or obesity, in particular type II diabetes.
  • a preferred species of the compounds of Formula I are compounds of the formula:
  • a preferred species of the compounds of Formula I are compounds of the formula:
  • X is CH; X18674
  • R 2 is H
  • R a is F
  • R a is CF 3 ;
  • R and R are independently selected from F and methyl or combine to form C 3 cycloalkyl
  • R and R are methyl or combine to form C 3 cycloalkyl
  • X is N and R and R c are methyl or combine to form C3 cycloalkyl
  • X is CH and R and R° are methyl or combine to form C3 cycloalkyl
  • R b and R c are methyl and R a is F;
  • R and R c combine to form C 3 cycloalkyl and R a is CF 3 .
  • Preferred compounds of the present invention include 5-[l-(2-Fluoro-2-methyl- propyl)-piperidin-4-ylmethoxy]- 1 '-methanesulfonyl- 1',2',3 ',6'-tetrahydro- [2,4']bipyridinyl; and 1 -Methanesulfonyl-4- ⁇ 4- [ 1 -( 1 -trifluoromethyl-cyclopropylmethyl)-piperidin-4- ylmethoxy] -phenyl ⁇ - 1 ,2,3 ,6-tetrahydro-pyridine.
  • C3-C5 cycloalkyl is taken to mean cyclopropyl, cyclobutyl and cyclopentyl.
  • Preferred C3-C5 cycloalkyl groups include cyclopropyl and cyclobutyl; another preferred group is cyclopropyl.
  • isomer 1 and isomer 2 relate to the specific enantiomers of final compounds or intermediates, “isomer 1” relating to the first compound to elute from the described chromatographic process and “isomer 2" the second. Where the term “isomer 1" or “isomer 2" is first attributed to an intermediate, the term is retained through to the final compound.
  • salts refers to salts of the compounds of the present invention which are substantially non-toxic to living organisms. Such salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et ah, Handbook of Pharmaceutical Salts: Properties Selection and Use, (VCHA/Wiley-VCH, 2002); and J. Pharm. Sci. 66, 2-19 (1977). Preferred
  • pharmaceutically acceptable salts include hydrochloride, mesylate and fumerate; more preferred salts are hydrochloride and mesylate.
  • the compounds of the present invention are preferably formulated as
  • compositions administered by a variety of routes are for oral administration.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (A, Gennaro, et ah, eds., 19 th ed., Mack Publishing Co., 1995).
  • Preferred pharmaceutical compositions include a compound of the present invention admixed with vehicle selected from the group consisting of 0.5 M phosphoric acid (100 mg/ml maximum concentration); hydroxyethylcellolose (1% w/v), polysorbate 80 (0.25% v/v), antifoam (0.05% v/v) and deionised water (110 mg/ml maximum concentration); and vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) (10% v/v), antifoam (0.05% v/v) and deionised water (250 mg/ml maximum concentration).
  • vehicle selected from the group consisting of 0.5 M phosphoric acid (100 mg/ml maximum concentration); hydroxyethylcellolose (1% w/v), polysorbate 80 (0.25% v/v), antifoam (0.05% v/v) and deionised water (110 mg/ml maximum concentration); and vitamin E TPGS (d-alpha-tocopheryl poly
  • the present compounds are administered in combination with one or more therapeutic ingredients.
  • therapeutic ingredients include for example metformin or a DPPIV inhibitor e.g. sitagliptin.
  • Administration in combination includes simultaneous, separate or sequential administration.
  • the compounds of the present invention are simultaneously, separately or sequentially administered with metformin.
  • the compounds of the present invention are simultaneously, separately or sequentially administered with sitagliptin.
  • Suitable protecting groups include those described in T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1991, hereafter referred to as “Greene”. Greene indicates appropriate conditions for "protection” and “de- protection” of suitable protecting groups to be used by the skilled artisan.
  • the intermediates and final products of the present invention may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.
  • the compound names for the Examples of the present invention are generated using AutoNom 2000.
  • DMEM Dulbecco's Modified Eagle's Medium
  • HTRF Homogenous Time-Resolved Fluorescence
  • PBS Phosphate Buffered Saline
  • IBMX Isobutylmethylxanthine
  • BSA Bovine Serum Albumin
  • FBS Fetal Bovine Serum
  • EBSS Earle's Balanced Salt Solution
  • EDTA Ethylene Diamine Tetraacetic Acid
  • NADPH means Nicotinamide Adenosine Dinucleotide Phosphate
  • HEC Hydroxyethyl Cellulose
  • LC-ESI/MS means Liquid Chromatography - Electrospray Ionization Mass Spectrometry
  • Pg means Protecting Group
  • Tf trifluoromethyl sulfonyl
  • Ts means para-toluene sulfonyl
  • Ms Liquid Chromatography - Electrospray Ionization Mass Spectrometry
  • R 1 CR a R b R c
  • the starting hydroxyl (a) is reacted with a mesylate bearing a piperidine with an appropriate protecting group such as carboxylic acid tert-butyl ester and a suitable base such as potassium carbonate in a suitable solvent such as acetonitrile at elevated temperature.
  • the isolated product is de-protected under conditions well known to the skilled artisan to provide compound (b).
  • Compound (b) is reacted with an aldehyde under standard reductive amination conditions, with a suitable reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as dichloromethane to provide the final compound (I).
  • compound (b) is reacted with an appropriately substituted acid using a coupling reagent such as o-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate and a suitable base such as diisopropylethylamine in a suitable solvent such as dimethylformamide at elevated temperature.
  • a coupling reagent such as o-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • a suitable base such as diisopropylethylamine in a suitable solvent such as dimethylformamide at elevated temperature.
  • the isolated product is reacted with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran at elevated temperature to provide the final compound (I).
  • Alternatively compound (b) is reacted with ROY and a suitable base such as potassium carbonate in
  • the starting piperidine (b) is reacted with 2,2-dimethyloxirane under an inert atmosphere such as nitrogen in a suitable solvent such as methanol.
  • a suitable fluorinating agent such as bis(2-methoxyethyl)aminosulfur trifluoride in a suitable solvent such as dichloromethane to provide the final compound
  • the starting piperidin-4-ol (c) is reacted with methanesulfonyl chloride and a suitable base such as triethylamine or pyridine in a suitable solvent such as
  • the starting piperidone (f) is mixed with a suitable base such as lithium diisopropylamide in a suitable solvent such as tetrahydrofuran at reduced temperature and reacted with N-phenylbis(trifluoromethanesulfbnimide) to provide the compound (g).
  • a suitable base such as lithium diisopropylamide
  • a suitable solvent such as tetrahydrofuran at reduced temperature
  • N-phenylbis(trifluoromethanesulfbnimide) to provide the compound (g).
  • the tetrahydro-pyridine compound (g) is reacted with bis(pinacolato)diboron, (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) chloride, 1,1'- bis(diphenylphosphino)ferrocene, and potassium acetate in a suitable solvent such as 1,4- dioxane at elevated temperature to provide the compound (h
  • the starting bromide is reacted with a boronate compound (h) bearing an appropriate protecting group such as carboxylic acid tert-butyl ester, a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium and a suitable base such as cesium carbonate in a suitable solvent such as dioxane/water at elevated temperature.
  • a suitable solvent such as dioxane/water at elevated temperature.
  • the isolated product is de-protected under conditions well known to the skilled artisan to provide compound (i).
  • Compound (i) is reacted with methanesulfonyl chloride and a suitable base such as triethylamine in a suitable solvent such as dichloromethane to provide the compound (j).
  • Y is OCH 3 an additional deprotection X18674
  • R' CR a R b R c
  • Methanesulfonyl chloride (21.91 g, 14.81 mL, 191.30 mmol) is added slowly (10 min) to a solution of 4-(4-bromophenyl)-4-piperidinol (50.00 g, 191.30 mmol) and triethylamine (29.04 g, 40.00 mL, 286.95 mmol) in tetrahydrofuran (575 mL) at 23 0 C
  • tris(dibenzylideneacetone)dipalladium (0) (1.36 g, 1.49 mmol) is purged with nitrogen, and then deoxygenated 1,4-dioxane (150 mL) and deoxygenated water (150 mL) are added. The mixture is stirred at 100 0 C for 1 h. The mixture is cooled to 23 0 C and 1 M aq hydrochloric acid is added until pH 2-3. The aqueous layer is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain a red solid. Diethyl ether is added and the solid is filtered to obtain 16 g of the title compound as an off-white solid. MS (m/z) 254 (M+l).
  • Methanesulfonyl chloride (29.26 g, 19.77 mL, 255.47 mmol) is added slowly (10 min) under nitrogen atmosphere to a solution of tert-butyl 4-(hydroxymethyl)piperidine- 1-carboxylate (50.00 g, 232.24 mmol) and triethylamine (35.25 g, 48.56 mL, 348.36 mmol) in anhydrous dichloromethane (700 mL) at 9 0 C (internal temperature). The mixture is stirred at 23 0 C for 16 h. The reaction mixture is successively washed with 1 M aq hydrochloric acid, water, and brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain 60 g of the title compound as a white solid. MS (m/z) 316 (M+23). X18674
  • Trifluoroacetic acid (2.98 g, 1.97 mL, 26.10 mmol) is added to a solution of 4-[4- (l-methanesulfonyl-l,2,3,6-tetrahydro-pyridin-4-yl)-phenoxymethyl]-piperidine-l- carboxylic acid tert-butyl ester (1.20 g, 2.61 mmol) in dichloromethane (13 mL). The mixture is stirred at 23 0 C for 30 min. 2 M aq. sodium hydroxide is added. The resulting white precipitate is filtered and washed with water. The mother liquor is extracted with dichloromethane.
  • the title compound is prepared essentially by the method of Preparation 1 (step 1) using 5-bromo-r,2',3',6'-tetrahydro-[2,4']bipyridinyl-r-ium; dihydrochloride salt as starting material. MS m/e ( 79 Br/ 81 Br) 316/318 (M+l).
  • the title compound is prepared essentially by the method of Preparation 1 (step 3) using 5-bromo-r-methanesulfonyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyl as starting material. MS (m/z) 255 (M+l).
  • the title compound is prepared essentially by the method of Preparation 2 (step 2) using r-methanesulfonyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyl-5-ol as starting material. MS (m/z) 452 (M+l).
  • Anhydrous dichloromethane (3 mL) and a 70% w/w solution of hydrogen fluoride (2.68 mL, 20.44 mmol) in pyridine are mixed in a polyethylene bottle at 0 0 C under a nitrogen atmosphere.
  • a solution of l-oxa-spiro[2.4]heptane-2-carbonitrile (3.30 g, 26.76 mmol) in anhydrous dichloromethane (3.2 mL) is added slowly.
  • the reaction is stirred at 0 0 C for Ih and at room temperature for Ih.
  • the mixture is cooled at 0 0 C and a saturated solution of sodium carbonate is added carefully.
  • the aqueous layer is extracted with diethyl ether.
  • a solution 25% of sodium hydroxide (7.00 mL, 72.8 mmol) in water is added to a solution of (l-fluoro-cyclopentyl)-hydroxy-acetonitrile (0.50 g, 3.5 mmol) in ethanol (10 mL) and the reaction is stirred at room temperature for 15 min.
  • the mixture is diluted with water and diethyl ether and the aqueous layer is extracted with diethyl ether.
  • the organic layers are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under vacuum to obtain 430 mg of a yellow oil that is used without further purification.
  • Diisopropylethylamine (1.60 g, 2.16 mL, 12.40 mmol) is added to a suspension of Preparation 2 (1.60 g, 4.13 mmol), o-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (1.99 g, 6.20 mmol) and 2-fluoro-2-methyl-propionic acid (0.48 g, 0.54 mL, 4.55 mmol) in anhydrous dimethylformamide (20 mL) and the mixture is stirred at 40 0 C for 1 h.
  • the reaction mixture is diluted with ethyl acetate and washed successively with 1 M aqueous hydrochloric acid, water, and 2 M aqueous sodium hydroxide.
  • the organic layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed.
  • the residue is purified by silica gel chromatography on a silica gel cartridge eluting with dichloromethane: ethyl acetate 0%, 5% then 10% to obtain 1.0 g of the title compound as a pale brown solid.
  • Preparation 6 (47 g, 114.5 mmol) is dissolved in 2 M aqueous solution of sodium hydroxide (500 mL) and extracted with dicloromethane (2 x 500 mL). The organic layer is dried over magnesium sulphate, filtered and evaporated to obtain 40 g of the title compound as a light yellow solid. MS (m/z) 352 (M+ 1).
  • dichloromethane (155 mL) is added bis(2-methoxyethyl)aminosulfur trifluoride (16.63 mL; 85.70 mmoles) at an internal temperature of 22-23 0 C. The reaction is stirred at 25 0 C for 2 h. Aqueous saturated solution of sodium bicarbonate is added to pH 7. Layers are separated, the aqueous layer is extracted with dichloromethane (2 x 500 mL), the combined organic layers are dried over magnesium sulphate, filtered and concentrated. The crude material is purified by silica gel chromatography eluting with 98:2 dichloromethane:methanol. The solid is triturated with 500 mL of methyl /-butyl ether X18674
  • Methanesulfonyl chloride (223.5 g, 1.95 mol) is added slowly at 0-5 0 C. The mixture is stirred at ⁇ 5 0 C for 1.5h. 1050 mL of 0.5 N solution of aq. hydrochloride are added to the mixture dropwise at 0-15 0 C and the resulting solution is stirred for 30 min. Layers are separated and the organic layer is washed with 1050 mL of water and concentrated to dryness. 700 mL of methyl tert-butyl ether are added and the mixture is refluxed for 0.5 h. After the mixture is slowly cooled to ⁇ 5 0 C, the suspension is filtered. The solid is stirred with 500 mL of methyl tert-butyl ether and filtered to dryness to provide 434 g of an off-white solid with 98.6% HPLC purity.
  • 4-(r-Methanesulfonyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yloxymethyl)- piperidine is suspended in 800 mL of methanol and added to an autoclave with a mechanical stirrer. 1500 mL of methanol are added and then dimethyloxirane (117 g, 1.62 mol) is added. The mixture is stirred at 60 ⁇ 70°C for 88 h, cooled to 25-30 0 C and concentrated to -1000 mL. The mixture is heated at 60-70 0 C and 4200 mL of water are added.
  • deoxofluor (173 g, 0.74 mol) is dissolved in 1250 mL of dichloromethane and cooled to -30— 40 0 C.
  • the solution of 1- [4-(r-methanesulfonyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yloxymethyl)-piperidin-l-yl]- 2-methyl-propan-2-ol in dichloromethane is added to this solution while maintaining the X18674
  • Step 2 Prepared essentially as Preparation 2 (step 2) using 4-methanesulfonyloxymethyl- piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(l-methanesulfonyl-l,2,3,6- tetrahydro-pyridin-4-yl)-phenol as starting materials. MS (m/z) 414 (M-55).
  • Step 2 Prepared essentially as Preparation 6 (step 2) using 4-[2-fluoro-4-(l- methanesulfonyl- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)-phenoxymethyl] -piperidine- 1 - carboxylic acid tert-butyl ester as starting material. MS (m/z) 369 (M+ 1).
  • Example 2 Prepared essentially as Example 2 starting from 4-[3-fluoro-4-(piperidin-4- y lmethoxy)-pheny 1] - 1 -methanesulfony 1- 1,2,3, 6-tetrahy dro-pyridine hydrochloride s alt and 2-fluoro-2-methyl-propionic acid. MS (m/z) 443 (M+l).
  • Diisopropyl azodicarboxylate (27.43 g; 128.87 mmol) is added to a solution of triphenylphosphine (33.80 g; 128.87 mmol) in dry tetrahydrofuran (330 mL) at 0 0 C.
  • the reaction is stirred for 20 min.
  • a suspension of [l-(l-trifluoromethyl-cyclopropylmethyl)- piperidin-4-yl] -methanol (24 g; 99.13 mmol), Preparation 1 (25.89 g; 99.13 mmol) in dry tetrahydrofuran (200 mL) is added dropwise.
  • Example 10 An alternative method for the preparation of Example 10 is as follows:
  • Lithium aluminum hydride (208 g, 5.0 eq) is suspended in 3.9 L of methyl tert- butyl ether and the suspension is stirred for 10 min.
  • a solution of l-(l-trifluoromethyl- cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (260 g, 0.93 mol) in 1.3 L of methyl tert-butyl ether is added dropwise at ⁇ 30 0 C. The mixture is refluxed for 20 h and cooled to 0-10 0 C. 500 mL of water are added at 0-10 0 C and the mixture is stirred for 30 min.
  • the suspension is filtered and the cake is washed with 1.8 L of methyl tert-butyl ether.
  • the filtrate is concentrated to - 3 L of volume at ⁇ 35 0 C under vacuum.
  • the solvent is displaced with tetrahydrofuran (1.0 L x 2) and concentrated to provide 212 g of the title compound in 96.8% purity.
  • Preparation 1 (197.8 g, 0.781 mol) is dissolved in 1.8 L of dimethylformamide and cooled to 0-10 0 C.
  • a solution of potassium tert-butoxide (87.6 g, 0.781 mol) dissolved in 1.6 L of dimethylformamide is added dropwise to the solution and the mixture is stirred at 20 ⁇ 30 °C for 30 min.
  • dimethylformamide is added dropwise to the solution.
  • the mixture is heated at -60 0 C and stirred for 1.5 h. It is cooled to 30-40 0 C, and 4.4 L of water are added dropwise.
  • the mixture is stirred at 30 0 C for 1 h and filtered. This process is done with the two batches of [1 -(I -trifluoromethyl-cyclopropylmethyl)-piperidin-4-yl] -methanol and the resulting cakes are combined for purification.
  • the cake is washed with 800 mL of a 1: 1 mixture of dimethylformamide and water.
  • the solid is stirred with 4 L of dichloromethane and filtered.
  • T-RExTM Tetracycline-Regulated Expression
  • Agonists to the human GPRl 19 receptor are characterized by measuring increases in the cAMP levels in 293 T-RExTM cells expressing hGPRl 19. 10,000 cells/well are seeded into a 96-well plate and cultured for 24h in DMEM supplemented with 10% fetal bovine serum, 15 ⁇ g/mL Blasticidin and 200 ⁇ g/mL Hygromycin B. Next day, cells are stimulated with 1 ng/mL Doxycycline in DMEM with no further addition of Hygromycin B and Blasticidin. cAMP assay is performed after 18 h incubation with doxycycline. cAMP is determined using the cAMP HiRange HTRF assay (Cisbo International).
  • Example 1 has an EC50 value of 4.61 nM;
  • Example 6 has an EC50 value of 0.95 nM;
  • Example 7 has an EC50 value of 2.13 nM;
  • Example 8 has an EC50 value of 1.10 nM; and
  • Example 10 has an EC50 value of 0.95 nM.
  • GLUTag cells are an immortalized murine intestinal enteroendocrine cell line that express the preproglucagon gene and secrete GLP-I in a regulated manner (Brubaker PL, Schloos J, Drucker DJ. Regulation of glucagon-like peptide- 1 synthesis and secretion in the GLUTag enteroendocrine cell line.
  • GLP-I content in the filtrate is determined with the Mouse/Rat Total GLP-I Assay (Meso Scale Discovery). The potency of the GPRl 19 agonists to stimulate GLP-I secretion is determined as the agonist concentration that gives 50% increase in GLP-I (EC50).
  • Examples 6 and 9 were tested essentially as described above and found to have respective EC50 value of 62.7 and 36.8 nM.
  • Blood samples (0.1 to 0.2 mL) are then collected using EDTA as an anticoagulant at 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 h. During the course of a study the total of blood (mL) collected is not to exceed 1% of total body weight in grams.
  • Example 6 was tested essentially as described above and found to have oral bioavailability of 90 % in Beagle dogs.
  • Example 10 was tested essentially as described above and found to have oral bioavailability of 53 % in Sprague Dawley rats.
  • vehicle 1% HEC
  • test article at 5 mL/kg. Animals are euthanized by CO 2 asphyxiation for 1 minute, and then blood is collected by cardiac puncture at various times (0.5, 1.5, 3, and 6 h post compound dose) into EDTA plasma tubes containing 10 ⁇ L/mL DPP4 inhibitor (
  • Example 3 Using the procedure essentially as described above, a 10 mg/kg dose of Example 3 resulted in an increase in GIP AUC over vehicle of 762 pg*h/mL; a 10 mg/kg dose of Example 10 resulted in an increase in GIP AUC over vehicle of 762 pg*h/mL; and a 1.6 mg/kg dose of Example 6 resulted in an increase in GIP AUC over vehicle of 422 pg*h/mL.
  • Certain compounds of the present invention have been shown to stimulate GIP secretion in vivo, which induces insulin secretion, such data indicates potential for use of compounds of the present invention in the treatment of diabetes.
  • glucose AUC Area under the plasma glucose curve
  • Example 6 was tested essentially as described above and found to demonstrate improved glucose tolerance. Example 6 did not influence fasting plasma glucose but significantly decreased postprandial plasma glucose. The data shows that the dose of Example 6 which produces a 50% decrease in glucose area under the curve (ED50) is equal to 0.4 mg/kg.
  • a compound of the present invention has been shown to decrease plasma glucose levels in vivo, indicating potential for use of the compounds of the present invention in the treatment of diabetes.
  • Animals are individually housed in a temperature-controlled (24 0 C) facility with 12 hour light, 12 hour dark cycle. Body weights range from 34 ⁇ 0 g.
  • Mice are administrated once daily vehicle (1% HEC), 30 mg/kg GPRl 19 agonist, 30 mg/kg DPPIV inhibitor or a combination of 30 mg/kg GPRl 19 agonist and 30 mg/kg DPPIV inhibitor. Treatment continues for 3 weeks. Food and body weights are recorded daily before dark photoperiod. Cumulative body weight change is calculated as the daily body weight minus body weight before treatment for each animal and presented as an average X18674
  • Example 6 was tested essentially as described above where the DPPIV inhibitor is sitagliptin. Sitagliptin alone did not alter body weight or food intake in the study.
  • Example 6 alone produced a mild decrease in both food intake and body weight observed only during the first week of treatment. Combination of sitagliptin and Example 6 produced profound decreases in body weight and food intake that were sustained throughout the course of the study. Example 6 alone or in combination with sitagliptin did not significantly modify plasma glucose levels in this model.
  • a compound of the present invention has been shown to decrease food intake and body weight, indicating potential for use of the compounds of the present invention in the treatment of obesity.

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NZ597125A NZ597125A (en) 2009-07-15 2010-07-12 Gpr119 agonists
BRPI1015921A BRPI1015921A2 (pt) 2009-07-15 2010-07-12 agonistas de gpr119
JP2012520691A JP5715127B2 (ja) 2009-07-15 2010-07-12 Ｇｐｒ１１９アゴニスト
CN201080031375.4A CN102471313B (zh) 2009-07-15 2010-07-12 Gpr119激动剂
KR1020127000996A KR101365854B1 (ko) 2009-07-15 2010-07-12 Ｇｐｒ119 효능제
MA34531A MA33428B1 (fr) 2009-07-15 2010-07-12 Agonistes du gpr119
MX2012000704A MX2012000704A (es) 2009-07-15 2010-07-12 Agonistas de gpr119.
CA2764906A CA2764906C (en) 2009-07-15 2010-07-12 Gpr119 agonists
SG2012002523A SG177646A1 (en) 2009-07-15 2010-07-12 Gpr119 agonists
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EP10734412A EP2454251A1 (en) 2009-07-15 2010-07-12 Gpr119 agonists
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IL216776A IL216776A0 (en) 2009-07-15 2011-12-05 Gpr119 agonists
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WO2012135570A1 (en) * 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170702A1 (en) * 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
WO2013048916A1 (en) * 2011-09-30 2013-04-04 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
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US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012135570A1 (en) * 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8957062B2 (en) 2011-04-08 2015-02-17 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2012170702A1 (en) * 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
US9006228B2 (en) 2011-06-16 2015-04-14 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds, and methods of treatment
US9422266B2 (en) 2011-09-30 2016-08-23 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2013048916A1 (en) * 2011-09-30 2013-04-04 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
US9018200B2 (en) 2011-10-24 2015-04-28 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as GPR119 agonists
US9018224B2 (en) 2011-11-15 2015-04-28 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds useful as GPR119 agonists
KR101535954B1 (ko) * 2012-06-12 2015-07-10 주식회사 종근당 Ｇｐｒ１１９ 활성의 효능제로서의 피페리딘 유도체
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
JP2015522559A (ja) * 2012-06-12 2015-08-06 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのピペリジン誘導体
EP2858986A4 (en) * 2012-06-12 2015-11-11 Chong Kun Dang Pharm Corp GPR119 AGONIST PIPERIDINE DERIVATIVES
JP2019104741A (ja) * 2012-06-12 2019-06-27 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのピペリジン誘導体
RU2603346C2 (ru) * 2012-06-12 2016-11-27 Чхон Кхун Дан Фармасьютикал Корп. Производные пиперидина в качестве агонистов gpr119
JP2017105785A (ja) * 2012-06-12 2017-06-15 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのピペリジン誘導体
CN104364246A (zh) * 2012-06-12 2015-02-18 株式会社钟根堂 用作gpr119激动剂的哌啶衍生物
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
WO2014052619A1 (en) * 2012-09-27 2014-04-03 Irm Llc Piperidine derivatives and compositions as modulators of gpr119 activity
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
EP3138834A4 (en) * 2014-05-02 2017-11-22 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method therefor, and pharmaceutical composition for preventing or treating metabolic diseases, containing same as active ingredient
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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